Research Article (New England Journal of Medicine) Four artemisinin-based treatments in African pregnant women with malaria

Background: Information regarding the safety and efficacy of artemisinin  combination treatments for malaria in pregnant women is limited, particularly among women who live in sub-Saharan Africa.Methods: We conducted a multicenter, randomized, open-label trial of treatments for malaria in pregnant women in four African countries. A total of 3428 pregnant women in the second or third trimester who had falciparum malaria (at any parasite density and regardless of symptoms) were treated with artemether–lumefantrine, amodiaquine–artesunate, mefloquine–artesunate, or dihydroartemisinin– piperaquine. The primary end points were the polymerase-chain-reaction (PCR)–adjusted cure rates (i.e., cure of the original infection; new infections during follow-up were not considered to be treatment failures) at day 63 and safety outcomes.Results: The PCR-adjusted cure rates in the per-protocol analysis were 94.8% in the artemether–lumefantrine group, 98.5% in the amodiaquine– artesunate group, 99.2% in the dihydroartemisinin–piperaquine group, and 96.8% in the mefloquine–artesunate group; the PCR-adjusted cure rates in the intention-to-treat analysis were 94.2%, 96.9%, 98.0%, and 95.5%, respectively. There was no significant difference among the amodiaquine–artesunate group, dihydroartemisinin–piperaquine group, and the mefloquine–artesunate group. The cure rate in the artemether–lumefantrine group was significantly lower than that in the other three groups, although the absolute difference was within the 5-percentage-point margin for equivalence. The unadjusted cure rates, used as a measure of the  post-treatment prophylactic effect, were significantly lower in the artemether–lumefantrine group (52.5%) than in groups that received amodiaquine–artesunate (82.3%), dihydroartemisinin–piperaquine (86.9%), or mefloquine–artesunate (73.8%). No significant difference in the rate of serious adverse events and in birth outcomes was found among the treatment groups. Drug-related adverse events such as asthenia, poor appetite, dizziness, nausea, and vomiting occurred significantly more frequently in the mefloquine–artesunate group (50.6%) and the amodiaquine–artesunate group (48.5%) than in the dihydroartemisinin–piperaquine group (20.6%) and the artemether–lumefantrine group (11.5%) (P<0.001 for comparison among the four groups).Conclusions: Artemether–lumefantrine was associated with the fewest adverse effects and with acceptable cure rates but provided the shortest posttreatment prophylaxis, whereas dihydroartemisinin–piperaquine had the best efficacy and an acceptable safety profile. (Funded by the European and Developing Countries Clinical Trials Partnership and others; ClinicalTrials.gov number, NCT00852423.

Four Artemisinin-Based Treatments in African Pregnant Women with Malaria.

BACKGROUND: Information regarding the safety and efficacy of artemisinin combination treatments for malaria in pregnant women is limited, particularly among women who live in sub-Saharan Africa. METHODS: We conducted a multicenter, randomized, open-label trial of treatments for malaria in pregnant women in four African countries. A total of 3428 pregnant women in the second or third trimester who had falciparum malaria (at any parasite density and regardless of symptoms) were treated with artemether-lumefantrine, amodiaquine-artesunate, mefloquine-artesunate, or dihydroartemisinin-piperaquine. The primary end points were the polymerase-chain-reaction (PCR)-adjusted cure rates (i.e., cure of the original infection; new infections during follow-up were not considered to be treatment failures) at day 63 and safety outcomes. RESULTS: The PCR-adjusted cure rates in the per-protocol analysis were 94.8% in the artemether-lumefantrine group, 98.5% in the amodiaquine-artesunate group, 99.2% in the dihydroartemisinin-piperaquine group, and 96.8% in the mefloquine-artesunate group; the PCR-adjusted cure rates in the intention-to-treat analysis were 94.2%, 96.9%, 98.0%, and 95.5%, respectively. There was no significant difference among the amodiaquine-artesunate group, dihydroartemisinin-piperaquine group, and the mefloquine-artesunate group. The cure rate in the artemether-lumefantrine group was significantly lower than that in the other three groups, although the absolute difference was within the 5-percentage-point margin for equivalence. The unadjusted cure rates, used as a measure of the post-treatment prophylactic effect, were significantly lower in the artemether-lumefantrine group (52.5%) than in groups that received amodiaquine-artesunate (82.3%), dihydroartemisinin-piperaquine (86.9%), or mefloquine-artesunate (73.8%). No significant difference in the rate of serious adverse events and in birth outcomes was found among the treatment groups. Drug-related adverse events such as asthenia, poor appetite, dizziness, nausea, and vomiting occurred significantly more frequently in the mefloquine-artesunate group (50.6%) and the amodiaquine-artesunate group (48.5%) than in the dihydroartemisinin-piperaquine group (20.6%) and the artemether-lumefantrine group (11.5%) (P<0.001 for comparison among the four groups). CONCLUSIONS: Artemether-lumefantrine was associated with the fewest adverse effects and with acceptable cure rates but provided the shortest post-treatment prophylaxis, whereas dihydroartemisinin-piperaquine had the best efficacy and an acceptable safety profile. (Funded by the European and Developing Countries Clinical Trials Partnership and others; ClinicalTrials.gov number, NCT00852423.)

Seasonal Patterns of malaria and its Health Related Consequences Among Adolescent females in Rural Malawi

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Comparative efficacy of chloroquine and sulphadoxine - pyrimethamine in pregnant women and children: a meta-analysis

Objective: To compare the efficacy of chloroquine and sulphadoxine-pyremethamine against Plasmodium falciparum infection in pregnant women and in children from the same endemic areas of Africa, with the aim of determining the level of correspondence in efficacy determinations in these two risk groups. Methods: Meta-analysis of nine published and unpublished in vivo antimalarial efficacy studies in pregnant women and in children across five African countries. Results: Pregnant women (all gravidae) were more likely to be sensitive than children to both chloroquine (odds ratio: 2.07; 95% confidence interval: 1.5, 2.9) and sulphadoxine-pyrimethamine (odds ratio: 2.66; 95% confidence interval: 11.1, 6.7). Pregnant women demonstrated an almost uniform increased sensitivity for peripheral parasite clearance at day 14 compared with children. This finding was consistent across a wide range of drug sensitivities. Primigravidae at day 14 showed lower clearance to antimalarial drugs than multigravidae (P < 0.05). There was no significant difference between parasite clearance in primigravidae and in children. Conclusion: The greater drug sensitivity in pregnant women probably indicates differences in host susceptibility rather than parasite resistance. Parasite sensitivity patterns in children may be a suitable guide to antimalarial policy in pregnant women

Trends in pregnancy outcomes in Malawian adolescents receiving antimalarial and hematinic supplements

Abstract Objective. To describe pregnancy outcomes of adolescent and adult primigravidae receiving antimalarials and hematinic supplementation and compare findings with a survey in this area a decade earlier. Design. Cross-sectional surveys in intervention and control sites. Setting. Community, antenatal and delivery facilities in Chikwawa, Malawi. A rural area with year round malaria transmission. Methods. Data on antenatal attendance, uptake of intermittent preventive treatment with sulfadoxine-pyrimethamine (IPTp-SP), birthweight, malaria, anaemia, for 2,152 primigravidae. Outcome measures. Place of delivery, anaemia, malaria, birthweight. Results. Fewer adolescent than adult primigravidae received >/=2 IPTp-SP doses (66 vs. 77.2%, p < 0.001), although more attended for two or more antenatal visits (92.0 vs. 76.7%, p < 0.001). Only 24.1% of adolescent primigravidae attended for hospital delivery. Women resident in intervention sites receiving IPTp-SP community distribution were more likely to choose a community delivery (p < 0.01), and have higher uptake of IPTp-SP (p = 0.036) than women not resident in these villages. Postnatal malaria prevalence was low and did not differ by age or place of delivery. Postnatal anaemia and low birthweight prevalence were higher in adolescents with community deliveries. Maternal anaemia and low birthweight prevalence were lower amongst adolescents in this study compared to estimates from the same population a decade previously. Conclusions. Adolescents had higher anaemia risk, lower IPTp-SP uptake than adults and under a quarter had a hospital delivery. Pregnancy outcomes improved compared to the survey a decade earlier. Monitoring and surveillance is required to reinforce to policy makers the need to improve adolescent coverage for available interventions

Community-based distribution of sulfadoxine-pyrimethamine for intermittent preventive treatment of malaria during pregnancy improved coverage but reduced antenatal attendance in southern Malawi

To evaluate the impact of a 2-year programme for community-based delivery of sulfadoxine-pyremethamine (SP) on intermittent preventive treatment during pregnancy coverage, antenatal clinic attendance and pregnancy outcome. Fourteen intervention and 12 control villages in the catchment areas of Chikwawa and Ngabu Government Hospitals, southern Malawi, were selected. Village-based community health workers were trained in information, education and counselling on malaria control in pregnancy and the importance of attending antenatal clinics and promoted these messages to pregnant women. In the intervention group community health workers also distributed SP to pregnant women. In the control area, coverage of intermittent preventive treatment during pregnancy (> 2 doses) was low before (44.1%) and during the intervention (46.1%). In the intervention area, coverage increased from 41.5% to 82.9% (P 2 visits) was maintained in control villages at above 90%, but fell in intervention villages from 87.3% to 51.5% (P 40% did not significantly improve maternal haemoglobin or reduce low birthweight prevalence. Better coverage of community-based intermittent preventive treatment during pregnancy can lower attendance at antenatal clinics; thus its effect on pregnancy outcome and antenatal attendance need to be monitored

Safe and efficacious artemisinin-based combination treatments for African

BACKGROUND: Asymptomatic and symptomatic malaria during pregnancy has consequences for both mother and her offspring. Unfortunately, there is insufficient information on the safety and efficacy of most antimalarials in pregnancy. Indeed, clinical trials assessing antimalarial treatments systematically exclude pregnancy for fear of teratogenicity and embryotoxicity. The little available information originates from South East Asia while in sub-Saharan Africa such information is still limited and needs to be provided. DESIGN: A Phase 3, non-inferiority, multicentre, randomized, open-label clinical trial on safety and efficacy of 4 ACT when administered during pregnancy was carried out in 4 African countries: Burkina Faso, Ghana, Malawi and Zambia. This is a four arm trial using a balanced incomplete block design. Pregnant women diagnosed with malaria are randomised to receive either amodiaquine-artesunate (AQ-AS), dihydroartemisinin-piperaquine (DHA-PQ), artemether-lumefantrine (AL), or mefloquine-artesunate (MQAS). They are actively followed up until day 63 post-treatment and then monthly until 4-6 weeks post-delivery. The offspring is visited at the time of the first birthday. The primary endpoint is treatment failure (PCR adjusted) at day 63 and safety profiles. Secondary endpoints included PCR unadjusted treatment failure up to day 63, gametocyte carriage, Hb changes, placenta malaria, mean birth weight and low birth weight. The primary statistical analysis will use the combined data from all 4 centres, with adjustment for any centre effects, using an additive model for the response rates. This will allow the assessment of all 6 possible pair-wise treatment comparisons using all available data. DISCUSSION: The strength of this trial is the involvement of several African countries, increasing the generalisability of the results. In addition, it assesses most ACTs currently available, determining their relative '-value-' compared to others. The balanced incomplete block design was chosen because using all 4-arms in each site would have increased complexity in terms of implementation. Excluding HIV-positive pregnant women on antiretroviral drugs may be seen as a limitation because of the possible interactions between antiretroviral and antimalarial treatments. Nevertheless, the results of this trial will provide the evidence base for the formulation of malaria treatment policy for pregnant women in sub-Saharan Africa.status: publishe